Human immunodeficiency virus type-1 (HIV-1) is a retrovirus that infects CD4+ T cells of the immune system. If left untreated, HIV-1 infected individuals will progress to AIDS and may ultimately die as a result. Combination antiretroviral therapy is extremely effective at stopping the replication of HIV-1 in infected individuals. Despit the success of this therapy at suppressing HIV-1 replication to clinically undetectable levels, antiretroviral therapy is not curative. This is due to the persistence of HIV-1 in a silent, or latnt, state within a subset of CD4+ T cells known as resting memory CD4+ T cells. In this latent state, these infected cells are not targeted by antiretroviral drugs and cannot be eliminated by the immune system. In HIV-1 infected individuals, latently infected CD4+ T cells are found at extremely low frequencies (~1 per million resting memory CD4+ T cells). However, this population of latently infected cells is very stable, demanding that HIV-1 infected individuals remain on antiretroviral therapy indefinitely. Therefore, this population of latently infected CD4+ T cells is the main barrier to curing HIV-1 infection. Developing strategies to eliminate latently infected cells is a major focus of the NIH, NIAID, and the HIV-1 research field. A leading proposal to eliminate these cells is the kick and kill approach. In this approach, latently infected cells are kicked out of their latent state by a drug that reactivates HIV-1 production. After these cells are reactivated, they can be killed by the immune system or by the cytopathic effects of the virus itself. Using in vitro models of HIV-1 latency, a number of candidate latency-reversing drugs have been identified. However, recent studies indicate that these agents do not substantially reverse latency in cells from HIV-1 infected individuals when used individually. Promisingly, our preliminary data indicate that combinations of these latency-reversing drugs are very effective on cells from HIV-1 infected individuals. This proposal aims to (1) optimize combinations of latency-reversing drugs, (2) determine whether treatment with these combinations leads to the death of latently infected cells, (3) help explain the discordance between laboratory model systems of latency and bona fide latently infected cells from HIV-1 infected individuals. Identifying combinations of effective latency-reversing drugs and understanding whether these combinations drive the elimination of latently infected cells is important to latency research and the future planning of clinical trials. Understanding the differences between model cells and bona fide latently infected cells will deepen our understanding of the maintenance of HIV-1 latency in infected individuals.